RBC 13 study document

I. Normal Red Blood Cell Physiology

1. Developmental Sites of Hematopoiesis

• Yolk Sac: Initial site in very early embryogenesis.

• Liver & Spleen: Predominant in newborns.

• Bone Marrow:

o Children: Active (red) marrow in axial and appendicular skeleton.

o Adults: Active marrow in axial skeleton only (appendicular skeleton has yellow

marrow).

2. Bone Marrow Features

2. Bone Marrow Features

• Cellularity: Ratio of hematopoietic cells to fat.

• Megakaryocytes: Platelet precursors.

• M:E Ratio: Normal myeloid to erythroid ratio ~3:1.

• Other Features:

o Myeloid & erythroid maturation.

o Plasma cells, lymphocytes, hemosiderin (storage iron), possible foreign cells.

3. Reference Ranges (Adults)

II. Anemias

Defined as reduced oxygen-carrying capacity of the blood. Can result from loss, destruction, or

decreased production of red cells.

General Features of Anemia

• Pallor (skin, mucosa)

• Fatigue, weakness

• Dyspnea (due to hypoxia)

• Palpitations, tachycardia

• High-output heart failure (compensatory)

III. Classification of Anemias, A. Blood Loss

A. Blood Loss

1. Acute:

• Due to trauma.

• Normocytic, normochromic anemia initially.

2. Chronic:

• GI lesions, gynecologic disturbances.

• Often presents like iron-deficiency anemia.

III. Classification of Anemias, B. Hemolytic Anemias (Increased Destruction)

B. Hemolytic Anemias (Increased Destruction)

Life span of RBCs <120 days, increased erythropoietin, marrow hyperplasia, elevated bilirubin, serum

HGB.

Types:

a) Hereditary:

• Membrane Defects: Hereditary spherocytosis.

• Enzyme Defects: G6PD deficiency.

• Hemoglobinopathies: Sickle cell disease, thalassemias.

b) Acquired:

• Membrane Defect: Paroxysmal Nocturnal Hemoglobinuria (PNH).

• Immune-mediated: Transfusion reactions, autoantibodies.

• Mechanical: Valves, microangiopathies (TTP, HUS).

• Drugs/Infections: Toxins, malaria, DIC.

Hemolysis Types:

• Intravascular: Within vessels; hemoglobinemia, hemoglobinuria.

• Extravascular: Spleen and liver.

Key Modifiers:

• MCV: Micro/macrocytosis

• MCH, MCHC: Hypochromia

• RDW: Anisocytosis

III. Classification of Anemias, C. Decreased Production (Impaired Erythropoiesis)

C. Decreased Production (Impaired Erythropoiesis)

Mechanisms:

• Stem cell disturbances (Aplastic anemia, pure red cell aplasia)

• DNA synthesis defects (B12, folate deficiency → megaloblastic anemia)

• Heme synthesis defects (iron deficiency)

• Globin synthesis defects (thalassemia)

1. Hereditary Spherocytosis

1. Hereditary Spherocytosis

• Autosomal dominant.

• Defective ankyrin, spectrin.

• Spherocytes, anemia, jaundice, splenomegaly, gallstones.

2. G6PD Deficiency

2. G6PD Deficiency

• X-linked recessive.

• Triggers: fava beans, infections, oxidant drugs.

• Heinz bodies, hemolysis, hemoglobinuria.

3. Sickle Cell Disease

3. Sickle Cell Disease

• HbS (β6 Glu→Val); autosomal recessive.

• Vaso-occlusion, pain crisis, autosplenectomy, infections.

4. Thalassemias

4. Thalassemias

• Impaired α or β globin synthesis.

• Microcytic, hemolytic anemia.

• Skull "crew cut" on x-ray.

o Hemoglobin H Disease: 3 α-globin gene deletions.

o Hydrops Fetalis: 4 α-globin gene deletions.

5. Paroxysmal Nocturnal Hemoglobinuria (PNH)

5. Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Acquired mutation in PIGA gene.

• Deficient GPI-anchored proteins → complement-mediated lysis.

6. Immunohemolytic Anemias

6. Immunohemolytic Anemias

• Antibodies against RBCs.

• Warm (IgG): idiopathic, malignancy, drugs.

• Cold Agglutinin (IgM): Mycoplasma, mono.

• Cold Hemolysin (IgG): Paroxysmal cold hemoglobinuria.

• Coombs Test:

o Direct: Detect Ab on RBC.

o Indirect: Detect Ab in serum.

V. Non-Hemolytic Anemias (↓ RBC Production) 1. Megaloblastic Anemias

V. Non-Hemolytic Anemias (↓ RBC Production)

1. Megaloblastic Anemias

Defective DNA synthesis, most commonly due to Vitamin B12 or Folate deficiency.

General Features:

• Macrocytic (MCV > 100)

• Hypersegmented neutrophils

• Bone marrow: megaloblasts

Vitamin B12 Deficiency (Pernicious Anemia)

Vitamin B12 Deficiency (Pernicious Anemia)

• Causes:

o ↓ intake (vegetarians),

o ↓ absorption (IF deficiency, gastrectomy, ileal disease)

o Tapeworm, blind loop syndrome

• Neurologic signs (posterolateral spinal cord demyelination)

• Low serum B12

• Failed Schilling test

• Achlorhydria

Folate Deficiency

Folate Deficiency

• Causes:

o Poor diet (alcoholics, infants)

o Drugs (methotrexate, anticonvulsants)

o Increased demand (pregnancy)

• No neurologic symptoms

2. Iron Deficiency Anemia

2. Iron Deficiency Anemia

• Most common anemia worldwide.

• Causes:

o ↓ intake (rare)

o ↑ loss (GI bleeding in men/postmenopausal women; menstruation in

premenopausal women)

• Microcytic, hypochromic

• Low serum ferritin

• Diagnosis:

o Serum ferritin (BEST test)

o Prussian blue stain of marrow (iron stores)

3. Anemia of Chronic Disease

3. Anemia of Chronic Disease

• Chronic infections, immune diseases, cancer, renal failure.

• Functional iron deficiency with abundant hemosiderin in marrow.

• Resembles iron-deficiency anemia.

4. Aplastic Anemia

4. Aplastic Anemia

• Pancytopenia due to stem cell failure.

• Idiopathic or caused by:

o Drugs (chloramphenicol, chemo)

o Viruses (EBV, Hepatitis, VZV)

o Radiation, insecticides

• Fanconi Anemia: Only inherited form.

• “Pure” red cell aplasia = only RBCs affected.

5. Myelophthisic Anemia

5. Myelophthisic Anemia

• Marrow failure due to space-occupying lesions, e.g., metastasis.

VI. Polycythemia

VI. Polycythemia

Types:

• Relative: Hemoconcentration (dehydration).

• Absolute:

o Primary (Polycythemia Vera): Myeloproliferative disorder; low EPO.

o Secondary: High EPO (hypoxia, tumors, EPO doping, high altitude).

VII. Bleeding Disorders (Hemorrhagic Diatheses)

VII. Bleeding Disorders (Hemorrhagic Diatheses)

Categories:

1. Blood vessel wall abnormalities

2. Platelet disorders:

o ↓ Number (thrombocytopenia)

o ↓ Function

3. Clotting factor deficiencies

4. DIC

A. Vessel Wall Abnormalities

A. Vessel Wall Abnormalities

• Infectious: Meningococcemia, RMSF

• Immune/Drug: Vasculitis

• Hereditary:

o Ehlers-Danlos

o Hereditary hemorrhagic telangiectasia

• Other: Scurvy, amyloid, Cushing

B. Thrombocytopenias

B. Thrombocytopenias

Mechanisms:

• ↓ Production (aplastic anemia, leukemia, drugs, viruses)

• ↑ Destruction (ITP, DIC, drugs, HIV)

• Sequestration (hypersplenism)

• Dilutional (massive transfusion)

Immune Thrombocytopenic Purpura (ITP)

Immune Thrombocytopenic Purpura (ITP)

• Chronic ITP: Adults, autoimmune

o Anti-platelet antibodies

o ↑ megakaryocytes in marrow

o Rx: Steroids

• Acute ITP: Children, post-viral, self-limited

Drug-Induced Thrombocytopenia:

Drug-Induced Thrombocytopenia:

• Quinine, quinidine, sulfa, heparin

HIV:

• Causes both decreased production and increased destruction.

C. Thrombotic Microangiopathies

C. Thrombotic Microangiopathies

• TTP (Thrombotic Thrombocytopenic Purpura)

• HUS (Hemolytic Uremic Syndrome)

• Both involve:

o RBC fragmentation

o Platelet consumption

o High mortality

D. Qualitative Platelet Disorders

D. Qualitative Platelet Disorders

• Inherited:

o Bernard-Soulier (GpIb deficiency)

o Glanzmann thrombasthenia (GpIIb/IIIa deficiency)

o Storage pool diseases

• Acquired: Aspirin use (irreversible COX inhibition)

E. Clotting Factor Deficiencies

E. Clotting Factor Deficiencies

Congenital:

• Hemophilia A: Factor VIII deficiency, X-linked

• Hemophilia B: Factor IX deficiency (Christmas disease), X-linked

Acquired:

• Vitamin K deficiency: Affects Factors II, VII, IX, X

• Liver disease: Impaired synthesis of clotting factors

F. von Willebrand Disease

F. von Willebrand Disease

• Most common inherited bleeding disorder (1%)

• Autosomal dominant

• ↓ vWF → defective platelet adhesion and low Factor VIII

• Prolonged bleeding time, normal platelet count

VIII. Disseminated Intravascular Coagulation (DIC)

VIII. Disseminated Intravascular Coagulation (DIC)

Widespread activation of coagulation → consumption of platelets and clotting factors → bleeding.

Causes:

• Obstetric complications (e.g., abruption, toxemia)

• Infections (e.g., meningococcemia)

• Malignancy (APL)

• Trauma, burns

Features:

• Widespread fibrin deposition

• Organ dysfunction

• High mortality

IX. Laboratory Tests Summary